Project Summary The Philadelphia chromosome-positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. To accomplish these goals, well-characterized mouse models of CML and B-ALL will be utilized to determine the mechanisms of pathogenesis of these diseases, to identify signaling pathways critical to leukemogenesis and to the genesis of leukemia-initiating or leukemia stem cels, and finally to validate these pathways as targets for therapy and conduct preclinical testing of molecularly targeted drugs. Together, these studies should yield important new knowledge that will improve the effectiveness of our current treatments for Ph+ leukemia, and increase the proportion of patients that are cured of their disease.